Hepatitis B Virus X Protein Induces Cellular Senescence and Autophagy

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Abstract

Hepatitis B virus (HBV) is a significant global threat to human health due to its
ability to cause chronic infections that can lead to hepatocellular carcinoma (HCC).
While the process by which HBV increases the risk of HCC is unclear, evidence suggests
that the hepatitis B X protein (HBx) may be a contributing factor. Cellular senescence is
an important barrier to tumorigenesis, blocking the proliferation of cells that harbor
excessive DNA damage or contain activated oncogenes. Autophagy is a non-proteasomal
degradative pathway used by cells to recycle cytoplasmic contents under periods of
nutrient starvation. This pathway is induced in response to a wide range of cellular stress
factors, and has also been characterized as an effector mechanism for the establishment of
cellular senescence. In this study, retroviral transduction of HepG2 cells with HBx
resulted in the induction of cellular senescence and autophagy. The mechanism by which
HBx can induce senescence is unclear. However, an increase in the accumulation of
DNA damage was observed. HBx did not modulate the levels of the anti-apoptotic
proteins Bcl-2, Bcl-xL, or Mcl-1, which can inhibit autophagy through interactions with
the autophagy regulator Beclin 1. As well, the activity and phosphorylation status of
JNK/SAPK, an inducer of autophagy via Bcl-2 phosphorylation, was unchanged. These
results suggest that senescence may act as a barrier to HBx-induced oncogenesis, and
may offer some explanation as to why HBx does not function as a more potent oncogene.
Also, we propose that HBx modulates autophagy through a mechanism other than Bcl-2
phosphorylation or expression over the time course of this study.